1. Field of the Invention
The invention relates to chiral amino alcohols and a process for their preparation. More particularly, the invention relates to 2-(dialkylamino)-1-methyl-4-(1-methylethenyl)cyclohexanols and 2-(alkylamino)-1-methyl-4-(1-methylethenyl)cyclohexanols and the preparation of the aforementioned chiral amino alcohols from a starting amine compound and a limonene oxide.
2. Description of the Prior Art
The following references are cited as prior art:
1. Patrick, R.; Newhall, W. F. J. Agr. Food Chem. 1960, 8, 397.
2. Kuczynski, H.; Zabza, A. Roczniki Chem. 1961, 35, 1621.
3. Kuczynski, H.; Zabza, A. Bull. Acad. Polon. Sci., Ser. Sci. Chim. 1961, 9, 551.
4. Kuczynski, H.; Zabza, A. Roczniki Chem. 1963, 37, 773.
5. Newhall, W. F. J. Org. Chem. 1964,29, 185.
6. Wylde, R.; Teulon, J. M. Bull Soc. Chim. Fr. 1970, 2, 758.
7. Kozhin, S. A.; Zaitsev, V. V.; Ionin, B. I. Zh. Obshch. Khim. 1978, 48, 203.
8. Pavia, A. A.; Geneste, P.; Olive, J. L. Bull. Soc. Chim. Fr. 1981, Part 2, 24.
9. Baker, R.; Borges, M.; Cooke, N. G.; Herbert, R. H. J. Chem. Soc., Chem. Commun. 1987, 414.
10. The following two structures have assigned CAS numbers, but no references were listed: p-Meth-8-en-1-ol, 2-piperidino-[92792-99-9]; Cyclohexanol, 1-methyl-4-(1-methylethenyl)-2-(1-piperidinyl)-, (1xcex1,2xcex2, 4xcex1)-[6756-83-8]
Newhall, U.S. Pat. No. 3,960,539
Newhall, U.S. Pat. No. 4,040,813
Reference 1 teaches the use of 2-dimethylamino-1-methyl-4-(1-methylethenyl)cyclohexanol (no stereochemistry indicated) as a plant fungicide. 
Reference 3 teaches the preparation of 2-dimethylamino-1-methyl-4-(1-methylethenyl)cyclohexanol from limonene oxide (there is some question about the stereochemistry presented in this paperxe2x80x94confusion exists in the literature as to what constitutes the cis and trans isomers of limonene oxide). This reference also reports the N-oxide of this amino alcohol.
Reference 4 also teaches the preparation of 3-dimethylamino-1-methyl-4-(1-methylethenyl)cyclohexanol from limonene oxide. This reference also teaches the preparation of the N-oxide of the dimethylamino compound.
Reference 5 teaches the reaction of limonene oxide with ammonia methylamine, and dimethylamine to give the corresponding amino alcohols. This reference also teaches the preparation of the N-oxide of the dimethylamino compound.
Reference 6 also teaches the reaction of dimethylamine with limonene oxide to give the corresponding amino alcohol.
Reference 7 teaches the reaction of limomene oxide with ammonia, methylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, and benzylamine to give the corresponding amino alcohols and their salts.
Reference 8 teaches the reaction of limonene oxide with dimethylamine to give the corresponding amino alcohol.
Reference 9 teaches the reaction of (R)-(+)-limonene oxide and (S)-(xe2x88x92)-limonene oxide with dimethylamine to give the corresponding amino alcohols.
U.S. Pat. Nos. 3,960,539 and 4,040,813 describe the preparation of compounds of the general formula 
and their use as plant growth regulators, nematocides, and fungicides.
The invention comprises a compound having the formula: 
in which R1 and R2 independently represent hydrogen or an alkyl group of 4 carbon atoms or greater. Further claimed is a process for the preparation of the disclosed chiral amino alcohols from a starting amine compound and a limonene oxide.
The invention comprises a compound having the formula: 
in which R1 and R2 independently represent a hydrogen or an alkyl group of 4 carbon atoms or greater, or in which R1 and R2 together form a carbocyclic ring containing five or more carbon atoms an which also may optionally contain a heteroatom selected from the group consisting of nitrogen, oxygen, or sulfur.
If R1 and R2 form a carbocyclic ring and n=1 or greater, then the following structure is created: 
in which X=NH, NCOOR (with Rxe2x95x90 to an alkyl group of from 1 to 6 carbon atoms), NCOR (with Rxe2x95x90 to an alkyl group of from 1 to 6 carbon atoms), NR (with Rxe2x95x90 to an alkyl group of from 1 to 6 carbon atoms, a benzyl or substituted benzyl group, or a phenyl or substituted phenyl group, or CHR (with Rxe2x95x90 to an alkyl group of from 1 to 6 carbon atoms, a benzyl or substituted benzyl group, or a phenyl or substituted phenyl group, or CO2H). The carbocyclic ring may optionally be fused to an aromatic ring to give compounds of the formula: 
In all cases, the stereochemistry of the compounds may be (1S,2S,4R) or (1R,2R,4S).
The invention also comprises compounds of the general formula: 
In which NR1R2 represents all of the amine combinations cited above.
The invention further comprises a process for preparing a chiral amino alcohol comprising the steps of providing an amine starting compound and a limonene oxide, refluxing the amine starting compound with the limonene oxide to form a chiral amino alcohol, removing excess amine and limonene oxide starting materials by distillation under reduced pressure of less than 10 Torr, forming the oxalate salt of the desired chiral amine by reaction of the crude product with oxalic acid in either methanol or acetone (or a mixture thereof), neutralizing the oxalate salt with aqueous potassium hydroxide, and purifying the desired amino alcohol by distillation or recrystallization.
In a preferred embodiment of the invention, the amine starting compound is selected from the group consisting of an alkyl amine with an alkyl group containing five or more carbon atoms, a dialkylamine containing alkyl groups containing five or more carbon atoms, a secondary amine in which the nitrogen is contained in a ring containing four or more carbon atoms (such amines include pyrrolidine, piperidine, hexamethyleneimine) and optionally may also contain a heteroatom consisting of the group including nitrogen, oxygen, and sulfur (such amines include morpholine, 4-methylpiperazine, 4-ethylpiperazine, ethyl 1-piperazinecarboxylate, and thiomorpholine). In addition, the amine may also contain a chiral center (such amines include (R)-alpha-methylbenzylamine, (S)-alpha-methylbenzylamine, (R)-1-cyclohexylethylamine, and (S)-1-cyclohexylethamine. The limonene oxide compound is preferably selected from the group consisting of (R)-(+)-limonene oxide or (S)-(xe2x88x92)-limonene oxide. As stated above, the amine starting compound is refluxed with the limonene oxide compound in the presence of water as a catalyst to form a chiral amino alcohol. The excess amine and limonene oxide are then distilled away at reduced pressure to give the crude amino alcohol. The crude amino alcohol is then treated with a solution of oxalic acid in either methanol or acetone (or a mixture thereof) to form the oxalic acid salt. The oxalic acid salt is isolated and may be further purified by recrystallization. The oxalate salt is neutralized with aqueous potassium hydroxide to give the desired amino alcohol. The amino alcohol may be purified by distillation or recrystallization as required. Optionally, after the reflux period is complete the reaction mixture is cooled to room temperature. The cooled reaction mixture is then dissolved in diethyl ether and the amino alcohol extracted into aqueous hydrochloric acid. The hydrochloric acid solution is then extracted with several of diethyl ether to remove any remaining limonene oxide. The amine is then converted to the free base form by neutralization of the aqueous hydrochloride solution with either sodium or potassium hydroxide. The amino alcohol is then extracted into diethyl ether and isolated by removal of the diethyl ether in vacuo (rotary evaporator). The amino alcohol is then purified by distillation or recrystallization as required.